Between 5-15% of individuals with severe hemophilia A develop inhibitors (alloantibodies) to FVIII. The development of an inhibitor has serious clinical consequences. The individual is no longer treatable with cryoprecipitate or commercial FVIII concentrates and must rely on far less effective and more costly modes of therapy which are associated with significant risk. Genetic factors are important in determining which individuals develop inhibitors, but the nature of those factors is poorly defined. It is the overall aim of this proposal to define the role that genetic factors including inherited idiotypes and the Gm and HLA series of immunoglobulin and white cell markers play in inhibitor development in severe hemophiliacs. To this end, we will attempt to develop monoclonal anti-idiotype reagents reactive with hemophilic anti-FVIII antibodies and study the inheritance of such idiotypes as well as the frequency of Gm and HLA antigens in individuals with and without inhibitors to FVIII. In addition, we will study the relationship of the above genetic markers to T Helper/supressor cell ratio abnormalities found in individuals with hemophilia.